This invention relates to a method for inhibiting the oxidation of lipoproteins, thereby slowing or stopping atherogenesis. The method entails the use of hydroxylated derivatives of known cholesterol lowering agents.
Atherosclerotic cardiovascular diseases and related conditions and disease events associated with hyperlipidemia are major causes of disability and death. It is now well recognized that lowering certain forms of cholesterol, both in healthy mammals as well as in individuals already experiencing states of hyperlipidemia, can dramatically reduce heart attacks, vascular disease, and other diseases associated with atherosclerotic conditions.
Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides, and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. There are five classifications of lipoproteins based on their degree of density: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL), and high density lipoproteins (HDL).
One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL cholesterol levels. The initial treatment for hypercholesterolemia is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when LDL-lowering goals are not met by diet and exercise alone. LDL is commonly known as the xe2x80x9cbadxe2x80x9d cholesterol, while HDL is the xe2x80x9cgoodxe2x80x9d cholesterol. Although it is desirable to lower elevated levels of LDL cholesterol, it is also desirable to increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD).
While LDL cholesterol is recognized as bad, and most cholesterol-lowering agents operate by lowering the plasma concentration of the LDL form, there is another key process in the early stages of atherogenesis, that being oxidation of LDL. Oxidation of VLDL and HDL also occurs, which also contributes to atherogenesis. Oxidation leads to increased intracellular calcium, lowered energy production, activation of cytokines, membrane damage, all resulting in apoptosis, necrosis, and ultimately cell death.
Oxidation typically begins when a reactive radical abstracts a hydrogen atom from a polyunsaturated fatty acid on the LDL particle. Lipid peroxyl and alkoxyl radicals are formed, which in turn can initiate oxidation in neighboring fatty acids, resulting in propogation of lipid peroxidation. These oxidized forms of lipoproteins are absorbed by macrophages more rapidly than the native lipoproteins, and this results in macrophage cholesterol accumulation, and subsequent foam cell formation and inhibition of the motility of tissue macrophages and endothelial cells. This cascade of events results in vascular dysfunction and formation and activation of atherosclerotic lesions.
We have now discovered that certain hydroxy-substituted derivatives of commonly employed cholesterol lowering agents are effective antioxidants for lipoproteins. Additionally, these compounds are useful for free radical scavenging and metal ion chelation, which also are mechanisms by which lipoproteins are oxidized.
This invention provides a method for inhibiting oxidation of lipoproteins in a mammal comprising administering an antioxidant effective amount of a hydroxylated cholesterol lowering agent. The invention also provides a method for scavenging free radicals in a mammal comprising administering a free radical scavenging amount of a hydroxylated cholesterol-lowering agent. The invention also provides a method for inhibiting metal ion chelation by lipoproteins comprising administering an effective amount of a hydroxylated cholesterol lowering agent.
In a preferred embodiment, the methods are practiced utilizing a hydroxylated form of a statin, especially atorvastatin, which compounds are described in U.S. Pat. No. 5,385,929, which is incorporated herein by reference.
In another preferred embodiment, the methods are practiced utilizing a hydroxylated gemfibrozil, e.g., a compound of the formula 
in another embodiment, a hydroxylated fluvastatin is employed, e.g., compounds of the formula 
In another embodiment, a hydroxylated cerivastatin is employed, especially a compound of the formula 
In another preferred embodiment, hydroxylated derivatives of lovastatin are employed, e.g., compounds of the formulas 